Disuse osteoporosis, a condition caused by chronic immobilization, results in decreased bone strength of the immobilized limb(s) and a corresponding increase in the risk of fracture (Frisbie, 1997; Garland et al., 1992; Smith, 2011). Disuse osteoporosis has been associated with individuals with spinal cord injury, stroke, multiple sclerosis, Parkinson's disease (Stage V), amyotrophic lateral sclerosis, poliomyelitis, Brown-Squard syndrome, cerebral palsy, traumatic brain injury, and more generally, individuals who exclusively use wheelchairs for mobility or are unable to leave their bed. In a study of individuals with spinal cord injury at the VA, treatment o these osteoporotic fractures required a mean hospital stay seven times longer than hospital stays for non-fracture admissions (Morse et al., 2009). Concurrently, treatment complications (i.e., non-union, pressure ulcers, pain, autonomic dysreflexia, heterotopic ossification) were observed in over half of all fracture cases. Considering the large proportion of fractures resultin from daily and/or therapeutic activities (Fattal et al., 2011; Ragnarsson & Sell, 1981) and the abundance of complications associated with disuse osteoporotic fractures, prophylaxis is nearly universally recommended as the paramount clinical intervention (Garland et al., 1992; Bauman et al., 2009; Logan et al., 2008). The long-term goal of this project is to reduce the incidence of fracture in individuals with disuse osteoporosis, specifically by addressing the unanswered clinical question, Are a particular patient's bones strong enough to participate in a prescribed activity, exercise, or therapy? (Kiratli, 2001). To address this goal, the following unmet need must be resolved: 1) a validated method for accurately estimating patient-specific bone strength for individuals with disuse osteoporosis; and 2) quantifying the internal forces imposed on at-risk skeletal sites during common daily and therapy-related activities. This study will address the firs unmet need by expanding the clinical capability of Dual energy X-ray Absorptiometry (DXA), the sentinel technology used for diagnosing osteoporosis, to compute mechanics-based parameters related to bone strength. Estimates of DXA-derived bone strength of the midshaft and distal femur subjected to bending and torsional loading (i.e., the most common fracture sites and fracture modalities observed for individuals with disuse osteoporosis) will be evaluated with mechanical testing of 65 cadaveric femora. We expect the derived structural parameters to be well correlated with absolute bone strength, as has been previously demonstrated at other skeletal sites using a mechanics-based approach and non-invasive imaging technology (Eckstein et al., 2004; Moisio et al., 2003; Siu et al., 2003). At the conclusion of this pilot sudy, 1) a critical barrier to progress in using DXA technology for deriving structural-based metrics will be eliminated by developing and validating a method for reconstructing pixel-by- pixel bone maps from raw DXA data for two common DXA scanning technologies (pencil and fan beam scanners); 2) the accuracy and precision of reconstructing engineering-based bone strength metrics using single, perpendicular, and triple-oriented DXA scans of the same bone will be determined; and 3) the predictive strength of using DXA-derived engineering-based metrics for estimating the measured bending and torsional strength of the midshaft and distal regions of the femur will be defined. A mechanics-based approach for estimating patient-specific bone strength has the potential to improve the specificity of identifying individuals at- risk of fractue when participating in common rehabilitation activities. We expect the personalized medicine approach to have the most benefit in aiding clinicians in identifying therapies and activities that will benefit patient health and also be of low-risk for causing a fracture in a given patient. Ultimately we believe this research will lead to a reduced fracture incidence in individuals with disuse osteoporosis. PUBLIC HEALTH RELEVANCE: Fractures in individuals with disuse osteoporosis, such as individuals with a spinal cord injury, predominantly occur during routine daily activities, passive stretching exercises, or other rehabilitation therapies and treatment of those fractures poses a high risk of complication. Although fracture prevention is the most widely accepted clinical intervention, there is currently no clinical method for assessing whether a patient's bones are strong enough to participate in a prescribed activity. The ultimate goal of this project is to produce a validated clinical tool for he diagnostic assessment of patient-specific fracture strength of individuals with disuse osteoporosis for evaluating the safe participation in specific daily and therapy-related activities This research will directly impact veterans who exclusively use wheelchairs for mobility, as well as those who are unable to leave their bed. We believe that the VA can and should play a central role in osteoporosis research, particularly in helping maintain quality of life, which can e severely affected following a disuse osteoporotic fracture.